Short-term effect of a moderate-potency topical corticosteroid on epidermal biophysical parameters in patients with mild-to-moderate atopic dermatitis: A randomised controlled study

Abstract Introduction: Skin barrier dysfunction is an important component of atopic dermatitis (AD) pathophysiology. Topical corticosteroids (TCSs) are the mainstay therapy, but steroid phobia is emerging due to potential side effects. We aimed to determine the short-term effect of clobetasone butyrate on patients with AD. Methods: This investigator-blinded, randomised, moisturiser-controlled study evaluated patients with stable mild-to-moderate AD. Clobetasone butyrate ointment plus aqueous cream (Aq) or Aq alone was applied on randomised sites twice daily for 6 weeks. The itch score, modified Eczema Area and Severity Index (M-EASI) and epidermal biophysical parameters were assessed at baseline and 1 h, 3 h, 2 weeks and 6 weeks after application. Results: Sixteen patients, among whom 14 (87.5%) were women and two (12.5%) were men, participated in the study. There were no significant differences in pH, transepidermal water loss (TEWL) and hydration between TCS + Aq and Aq from 1 h to 6 weeks. A non-significant trend of pH increment was observed with TCS + Aq from baseline to 6 weeks. TEWL and hydration improved at 6 weeks for both treatment arms. The difference in TEWL from baseline was significant with Aq (P=0.01). The M-EASI at 6 weeks was comparable between the two arms. TCS + Aq improved itch and erythema better than Aq (P=0.02). No cutaneous adverse effects were observed at both sites. Conclusion: Short-term application of clobetasone butyrate with Aq is safe with no significant changes in epidermal biophysical parameters while controlling the symptoms and signs of eczema faster than Aq alone.


Introduction
Atopic dermatitis (AD) is a chronic pruritic in ammatory skin disease that commonly occurs in children.Its prevalence is as high as 20% and continues to rise in both developed and developing countries. 1 epidermis of patients with AD is characterised by skin barrier dysfunction with increased transepidermal water loss (TEWL), less hydration and a surface pH that shifts towards alkalinity. 2 e magnitude of these dysfunctions correlates with the severity of the disease. 3pical therapy is the mainstay management for AD.Topical corticosteroids (TCSs) are the recommended rst-line anti-in ammatory agents in both children and adults. 4Local cutaneous adverse e ects of TCSs after prolonged use are well established.ese e ects include skin atrophy, hypopigmentation, telangiectasia, ecchymoses, striae and hypertrichosis.Adverse e ects due to systemic absorption of TCSs are rare.Tachyphylaxis may occur with TCS usage, while withdrawal of TCS therapy may lead to a rebound of AD symptoms. 5Concurrent use of topical skin barrier repair agents is advisable to reduce TCS requirements and counter the adverse e ects of TCSs on the stratum corneum. 6,7e adverse e ects of TCSs have led to steroid phobia among patients with AD and their caretakers, resulting in compliance issues leading to inadequate therapy and disease control. 8,9spite the established and well-recognised long-term adverse e ects of TCSs, information on the short-term e ects is sparse. 10,11s study aimed to assess the short-term e ects of a moderate-potency TCS on the epidermal biophysical characteristics of patients with AD, speci cally pH, TEWL, hydration and resolution of AD symptoms and signs.

Methods
We performed a 6-week randomised controlled study at a dermatology clinic in a teaching hospital.Patients who were diagnosed with AD according to the Hani n-Rajka criteria, 12 were aged 7-40 years, had mild-to-moderate disease severity based on a Eczema Area and Severity Index (EASI) 13 ranging from 1 to 21, had visible subacute or chronic lesions at symmetrical sites with no active skin infection or history of frequent infections and had been using TCSs either regularly or as needed and aqueous cream (Aq) with or without glycerine as a moisturiser were included in this study.Patients who were on systemic immunosuppressive or immunomodulating agents, were receiving phototherapy or had modi cations in their treatment regimen within 4 weeks of recruitment were excluded from the study.Informed consent was obtained from patients or guardians of patients aged <18 years.
Demographic and clinical characteristics were obtained through face-to-face interviews and patients' medical records.Physical examination was performed on all patients.e EASI was used to assess the overall AD severity. 13e eczematous lesion measuring 2-5 cm 2 on the left and another on the right were identi ed for intervention and assessment; they were symmetrical lesions on either the upper limbs, lower limbs or abdomen.
e lesion selected for TCS application was randomised using the sealed opaque envelope technique and treated with clobetasone butyrate ointment (U-Closone by HOE Pharmaceuticals) twice a day for 6 weeks.Clobetasone butyrate ointment is classi ed as a moderate-potency TCS in the Monthly Index of Medical Specialties and is the most commonly used moderate-strength TCS in our patients with AD. e lesion on the other side was not treated with any TCS.Both sides were moisturised twice a day using a standard Aq manufactured by KCK Pharmaceutical Industries with a pH ranging from 7.32 to 7.58 and without sodium laureth sulfate content.
e investigators were blinded to the allocation of therapy.A moisturiser was applied on both sides to conform with standard clinical practice.Patients were instructed to apply the TCS about half an hour after the application of the moisturiser.
ey were allowed to continue their routine AD treatments, including TCS or topical calcineurin inhibitor (TCI) in other areas.[16][17] e severity of eczema at the chosen sites was assessed using the M-EASI, whereby the total score was calculated without the inclusion of the body surface area.e itch score was measured based on lesional itch rather than overall itch using a visual analogue scale.
e itch score, M-EASI, skin pH, TEWL and hydration were evaluated at baseline and 1 and 3 h after TCS application.ese measurements were repeated after 2 and 6 weeks of regular TCS application.pH was measured using the HI99181 Skin pH Meter by Hanna Instruments, Padua, Veneto: Italy while TEWL was measured using Tewameter® TM300, Courage+Khazaka electronic GmbH, Köln: Germany.DermaLab Combo, Cortex Technology, Aalborg: Denmark was used to assess hydration.Patients were advised not to use any skin cleanser or apply any products on their skin for at least 12 h before the skin measurements and were acclimatised to the room environment for at least 15 min.e sample size was calculated using the PS Power and Sample Size Calculation software version 3.1.6based on the results of a previous study that compared the e ect between betamethasone dipropionate and a vehicle on TEWL. 18 response within each group in this study was normally distributed with a standard deviation of 2.3, and the di erence in the experimental and control means was 2.2.e estimated sample size was 18 per arm to be able to reject the null hypothesis that the means of the experimental and control groups are equal, with a probability (power) of 0.8 and a type I error probability of 0.05.Data were tabulated and analysed using the IBM® Statistical Package for the Social Sciences Statistics for Windows version 27.0, Armonk, NY: USA.Categorical data were presented as numbers and percentages.e Shapiro-Wilk test was utilised to determine the normality of continuous data.Continuous data were described as medians with interquartile ranges, as most were not normally distributed.
e Mann-Whitney U test was used to analyse paired numerical data where applicable.A P-value of <0.05 was considered statistically signi cant.

Results
A total of 16 patients with AD, including 14 (87.5%)women and two (12.5%)men, participated in the study.e median age at AD onset was 15 (22) years, and the median disease duration was 5.5 (20) years.e median EASI was 2.10 (2.66).irteen (81.3%) patients had a family history of atopy, and 13 (81.3%)had other atopic diseases, with the most common being allergic rhinitis (n=10, 12.82%).Five (31.3%) patients had a food allergy, while three (18.8%)had a drug allergy.
irteen (81.3%) patients were taking anti-histamines.e demographic, clinical and treatment characteristics of the study population are summarised in Table 1 E ects of the TCS on the epidermal biophysical parameters ere were no signi cant di erences in pH, TEWL and hydration at baseline between the TCS + Aq and Aq sites.No signi cant di erences in all biophysical parameters were also observed between the two sites from 1 h to 6 weeks of application (Tables 2 and 3).Tables 2. Comparison of the changes in the biophysical parameters from baseline to 1 and 3 h after application at the TCS + Aq and Aq sites.A non-signi cant trend of increment in pH from baseline to 6 weeks was observed at the TCS + Aq sites (Table 4).TEWL showed a progressive reduction from baseline to 6 weeks, which was also non-signi cant.Hydration initially decreased but was greater than the baseline by 6 weeks (P=0.38)(Table 4).e pH at the Aq sites was slightly lower than the baseline at 6 weeks (P=0.85),while TEWL showed a gradual reduction until 6 weeks (P=0.01).Similar to hydration at the TCS + Aq sites, the values initially decreased but became higher than the baseline by 6 weeks at the Aq sites (P=0.72)(Table 4).

Parameters
Tables 4. Biophysical parameters at the TCS + Aq and Aq sites from baseline to 6 weeks after application.

E ects of the TCS on the itch score and lesional severity
e redness score at the TCS + Aq sites showed an earlier reduction at 2 weeks (median=0 [1]) than that at the Aq sites (median=1 [0]) (P=0.002).At 6 weeks, both sites achieved resolution of redness.
ickness and scratching resolved within 2 weeks at both sites.No signi cant licheni cation was seen among the patients.e TCS + Aq sites showed better improvement at 2 weeks, with an itch score of 0.5 (2), than the Aq sites, with an itch score of 1.5 (2); however, the di erence was not statistically signi cant.Itching resolved at both sites by 6 weeks.ese ndings are summarised in Table 5. Skin atrophy, hypopigmentation, telangiectasia, hypertrichosis and folliculitis were not observed at the TCS application sites in all patients.
Tables 5. Itch score and disease severity.

Discussion
TCSs are the mainstay topical agents for treating AD, which are highly e ective in controlling cutaneous in ammation.e various types of TCSs are classi ed based on their potency.e occurrence of adverse e ects depends on the type, potency, duration of use and site of application of TCSs.Subclinical adverse e ects can be measured using various parameters including epidermal thickness, stratum corneum adhesion and integrity, surface pH, TEWL and hydration.5][16] Epidermal thinning may occur within 10 days to 4 weeks of regular application of betamethasone valerate and clobetasol propionate. 15,18,19Decreased stratum corneum adhesion and integrity have been demonstrated as early as 3 days with clobetasol 0.05%, a potent TCS. 14 However, improved TEWL and hydration and increased lamellar bodies were observed with the 3-week use of triamcinolone acetonide in a previous study, 15 while mometasone furoate increased ceramide levels after 12 weeks with no change in TEWL and hydration in another study. 16nother report indicated that the application of betamethasone valerate 0.1% cream twice per week for 8 weeks in patients with quiescent AD resulted in increased pH, unchanged TEWL and loss of stratum corneum cohesion but preserved stratum corneum integrity. 17[16][17][18][19] e skin's acid mantle is important in maintaining its normal structure and functions.
e physiologic pH of the stratum corneum ranges from 4.1 to 5.8 with small variations between the face, trunk and extremities. 20pH is increased by 0.2-0.3 units in AD lesions compared with non-lesional skin and by 0.2 units in non-lesional AD skin compared with healthy controls. 21Moisturisers with a physiological pH have been shown to improve skin barrier function compared with standard moisturisers with a higher pH, while skin cleansers with a low pH have been reported to improve disease severity in patients with AD. 22,23 Maintaining the skin pH on the acidic spectrum is bene cial in controlling AD.In the present study, we demonstrated that short-term use of clobetasone butyrate ointment with a standard Aq with a pH ranging from 7.32 to 7.58 did not alter the skin pH of our study population.Although a topical agent that reduces pH to physiological levels is more desirable, a TCS that does not alter pH is acceptable.
TEWL is a component of the skin barrier that is markedly a ected in AD.It is correlated with disease severity and gradually declines with clinical improvement. 2,3 e ects of TCSs on TEWL in patients with AD have been documented in a few studies.TEWL increment has been observed in atrophic skin following long-term use of highly potent TCSs. 10,11Shortterm application of clobetasol propionate, a potent TCS, has increased TEWL, reduced dermal and epidermal thickness and decreased the levels of epidermal ceramides, cholesterol and free fatty acids, which are important for maintaining epidermal integrity. 24Conversely, concurrent application of betamethasone valerate 0.1%, another potent TCS, with a moisturiser for 3 weeks has improved TEWL and hydration. 15However, epidermal thickness has been reduced, and the structures of lamellar bodies and the lipid bilayer have not been restored. 15Mometasone furoate cream, another potent TCS, used in combination with a moisturiser has increased ceramide levels and has not a ected TEWL and hydration after 12 weeks. 16A study on triamcinolone acetonide cream, a moderate-potency TCS, showed improved TEWL and hydration and a larger number of physiological lamellar bodies after 3 weeks. 15In our study, the use of a moderate-potency TCS with a moisturiser did not negatively impact TEWL but improved hydration.Moderate-potency steroids may exert a di erent e ect on epidermal characteristics compared with potent steroids; as demonstrated by previous reports and the present ndings, concomitant use of moisturisers may also play a role in in uencing the e ects of TCSs.Topical anti-in ammatory treatment for AD in combination with moisturisers has been shown to yield better results than monotherapy. 25oisturisers work synergistically with TCSs by enhancing their e ectiveness and playing a steroid-sparing role. 4,25Moisturisers prolong the time between AD ares, decrease the frequency of ares and reduce the amount of TCSs required for disease control. 25TCSs provide faster resolution of in ammation, while moisturisers repair and preserve the epidermal barrier.In our study, both arms achieved good symptom control, with TCS application demonstrating faster resolution of dermatitis.TCS application was more e ective than moisturiser application alone in lesion clearance.
e bene cial e ect of using moisturisers even as a monotherapy was observed.
In summary, short-term moderate-potency TCS application in patients with mild-to-moderate AD did not a ect the epidermal barrier parameters nor did it yield local cutaneous adverse e ects.TCS application resulted in faster recovery of the a ected skin than moisturiser application alone.
ese ndings can be used to reassure patients and caregivers, especially those with steroid phobia, that shortterm use of TCSs to control AD would not impair the skin barrier functions while achieving better symptom control and may improve their compliance in using moisturisers.
In our study, the patients were advised to comply with the study requirements including the topical applications; however, compliance was not objectively measured, which may be a limitation of this study.

Conclusion
Short-term application of a moderate-potency TCS with Aq for mild-to-moderate AD does not signi cantly change skin pH, TEWL and hydration while providing rapid relief of the symptoms and signs of eczema.ese ndings can reassure patients with AD that short-term use of TCSs is safe.As moisturiser monotherapy also improves eczema, moisturisers should be used with TCSs to optimise treatment bene ts and limit the adverse e ects of TCSs.

Table 3 .
Comparison of the changes in the biophysical parameters from baseline to 2 and 6 weeks after application at the TCS + Aq and Aq sites.